Diabetes is a major health care problem that has reached crisis proportions. The disease accounts for >14% of total national health care expenditures in the US and untold losses of precious human resources, and new therapies are urgently needed. Although glucose monitoring is central to all therapies for diabetes, present fingerstick methods and short-term percutaneous needle-like sensors are objectionable to many potential users, limiting their application. A new, more acceptable glucose sensor is urgently needed that could direct insulin dosing, warn of hypoglycemia, and serve as the missing component of a practical artificial pancreas. We have developed a new, fully implanted glucose sensor and wireless telemetry for long-term implantation in subcutaneous tissues. In studies with normal and diabetic pigs, we have a total of 31 cumulative device-years of implant experience, with 17 of the devices remaining functional for more than one year, and one implant functioning for 520 days (Sci. Trans. Med. 2, 42ra53, 2010). The sensor has also functioned successfully for six months in an initial human trial. The sensor incorporates a unique design in which glucose is monitored via a differential enzyme electrode detection principle that overcomes the limitations of implant encapsulation by the body. This sensor has fundamental advantages over other glucose sensors: users don't need to recalibrate or replace the sensor frequently, making continuous glucose monitoring and potentially the artificial pancreas much more acceptable to the general diabetic public. Although the sensor-telemetry system can function for at least one year and planned improvements may further extend its lifetime, the device will eventually have to be replaced. It is highly desirable to reuse the same implant site i possible, rather than creating multiple new implant sites over a lifetime. The questions to be addressed here are: Can an implant site be reused? What tissue response mechanisms are involved? The hypothesis to be tested is The implant site is reusuable. Previous studies showed that implant sites have fully stabilized within 8 weeks, indicating that an accelerated 12-week replacement test cycle in the pigs can correspond to a 1 to 2-year clinical replacement cycle. In this Phase I project, four sensor-telemetry units will be implanted in each of two pigs, and weekly glucose challenges will be performed. Devices will be exchanged every 12 weeks, and an extensive statistical analysis will determine whether effective monitoring can continue at the sites. Tissue permeability to glucose and oxygen will be assessed, extensive histologic examination will be performed, and mass transfer models will be constructed. If successful, these studies will provide a foundation for continuous glucose monitoring over a lifetime, with minimal obtrusiveness to people with diabetes.